The present invention relates generally to compounds having melatonin receptor activities and in particular to substituted derivatives of 2-amidotetralins, to pharmaceutical preparations comprising these compounds; to methods for using these compounds as therapeutic agents and to methods for using these compounds as diagnostic reagents.
Melatonin (N-acetyl-5-methoxytryptamine) is a hormone synthesized and secreted primarily by the pineal gland, with highest levels occurring during the dark period of a circadian light-dark cycle. The hormone is also found in the retina, and gut. The structure of melatonin is: ##STR1##
Melatonin is involved in the transduction of photoperiodic information and appears to modulate a variety of neural and endocrine functions in vertebrates, including the regulation of reproduction, body weight and metabolism in photoperiodic mammals, the control of circadian rhythms and the modulation of retinal physiology. Retinal melatonin has been implicated in photoreceptor outer segment disc shedding and phagocytosis, in melanosome aggregation in pigment epithelium, and cone photoreceptor retinomotor movement. Of the various physiological processes that have been associated with melatonin, those best substantiated are its effects on sexual maturation, ovarian function, and chronobiological rhythms. See Arendt, J., Oxford Reviews of Reproductive Biology, Vol. 8: 266-320 (1986) and Dubocovich, M. L., FASEB J., 2765-2773 (1988).
Exogenous melatonin administration has been found to synchronize circadian rhythms in rats. Cassone, et al., J. Biol. Rhythms, 1:219-229 (1986). In humans, administration of melatonin has been used to treat jet-lag related sleep disturbances, considered to be caused by desynchronization of circadian rhythms. Arendt, et al., Br. Med. J., 292:1170 (1986). Classically, the physiological effects of endogenous melatonin have been antagonized by exposure of animals to light, which inhibits the synthesis of melatonin, or by removal of the pineal gland.
Pharmacological studies have shown that picomolar concentrations of melatonin selectively inhibit the calcium-dependent release of dopamine from rabbit and chicken retina through activation of a site having the pharmacological and functional characteristics of a receptor. Dubocovich, M. L., Nature, 306:782-784 (1983). Dubocovich, M. L., Eur. J. Pharmacol., 105:193-194 (1984). Dubocovich, M. L., J. Pharmacol. Exp. Ther., 234:395-401 (1985). Using the radioiodinated ligand, 2-[.sup.125 I]iodomelatonin, which enhances the ability to detect melatonin receptor sites in vertebrate retina, a pharmacological correlation between the binding site labeled by 2-[.sup.125 I]iodomelatonin and a functional response regulated by melatonin in the chicken and rabbit retina has been demonstrated. Dubocovich, M.L., et al., Proc. Nat'l. Acad. Sci. USA, 84:3916 (1987). Using this radioligand, melatonin binding sites have been localized primarily in the suprachiasmatic nucleus and pars tuberalis/median eminence of mammals, including humans. Reppert, et al., Science, 242:78-81 (1988) and Duncan, et al., Endocrinol., 125:1011-1018 (1989). This is interesting because the melatonin receptor sites localized in the suprachiasmatic nucleus and/or median eminence/par tuberalis have been suggested to regulate circadian rhythms and reproductive function.
While the radioligand 2-[.sup.125 I] iodomelatonin is a useful probe for the localization and characterization of melatonin receptors, a significant problem in further elucidating the mechanism of action of melatonin is the lack of potent and selective melatonin receptor agonists and antagonists. Such agonists/antagonists could find application not only in the study of melatonin receptor interactions but also in the treatment of conditions possibly affected by melatonin activity, such as depression, jet-lag, disturbances in the sleep-wakefulness cycle, hypertension, glaucoma, reproduction and neuroendocrine disorders.
Generally, agonists of neurotransmitters and neurohormones are structurally related to the transmitter they mimic, whereas antagonists may be structurally unrelated and quite diverse. The term melatonin agonist is used herein to comprise compounds that mimic melatonin activity, e.g., melatonin inhibition of the calcium-dependent release of [.sup.3 H]dopamine evoked by electrical stimulation of chicken retina and rabbit retina. To date, all of the known melatonin agonists are derivatives of melatonin itself, e.g., 2-iodomelatonin, 6-chloromelatonin, 6,7-dichloro-2-methyl melatonin, and 8-hydroxymelatonin, and all contain the 5-methoxy indole ring system as an essential moiety. See, Dubocovich, et al., Proc. Nat'l. Acad. Sci. (USA), 84:3916-3918 (1987). Dubocovich, J. Pharmacol. Exp. Ther., 234:395 (1985).
As for melatonin antagonists, previous structure-activity studies on the melatonin receptor led to the suggestion that N-acetyltryptamine analogs lacking the 5-methoxy group might be potential melatonin receptor antagonists. Heward, et al., Life Sci., 17:1167-1178 (1975). Dubocovich, M. L., Eur. J. Pharmacol., 105:193 (1984). Dubocovich, et al., Proc. Nat'l. Acad. Sci. (USA), 184:3916 (1987). Dubocovich, M. L., J. Pharmacol. Exp. Ther., 234:395 (1985). However, while N-acetyltryptamine was reported to antagonize the melatonin-induced lightening of the .alpha.-melanocyte stimulating hormone-induced darkening of the frog skin, and to be a competitive melatonin receptor antagonist in chicken retina, it was found to be a partial melatonin agonist in rabbit retina. Heward, C. B., et al., Life Sci., 17:1167 (1975); Dubocovich, M. L., Eur. J. Pharmacol., 105:193 (1984). Dubocovich, M. L., J. Pharmacol. Exp. Ther., 234:395 (1985).
The first compound shown to be a competitive antagonist of mammalian melatonin receptors was luzindole (2-benzyl-N-acetyltryptamine). Dubocovich, M. L., J. Pharmacol. Exp. Ther., 246:902 (1988). Luzindole, in concentrations up to 10 .mu.M, does not modify either the spontaneous outflow or the calcium-dependent release of [.sup.3 H]dopamine, but does antagonize the ability of melatonin to inhibit [.sup.3 H]dopamine release in a competitive fashion. A variety of other compounds have been examined for possible antagonistic activity; however, none have shown the competitive antagonism seen with luzindole.
All of these known melatonin agonists and antagonists retain the 5-melatonin-indole ring system of the natural hormone melatonin. Historically, development of receptor agonists and antagonists which are chemically unrelated to the natural hormone or neurotransmitter has led to selective and potent therapeutic agents. However, there continues to exist a need in the art for such melatonin agonists and antagonists for use in investigating the physiological role of the hormone melatonin, and in treating disorders involving disturbances of the melatonin system. The present invention describes a non-indolic class of compounds which surprisingly show high melatonin agonist/antagonist activity.